Early photoreceptor outer segment loss and retinoschisis in Cohen syndrome

<p><b>Purpose</b>: To describe early structural and functional retinal changes in a patient with Cohen syndrome.</p> <p><b>Methods</b>: A 13-month-old Caucasian girl of Irish and Spanish ancestry was noted to have micrognathia and laryngomalacia at birth, which prompted a genetic evaluation that revealed biallelic deletions in <i>COH1 (VPS13B)</i> (a maternally inherited 60-kb deletion involving exons 26–32 and a paternally inherited 3.5-kb deletion within exon 17) consistent with Cohen syndrome. She underwent a complete ophthalmic examination, full-field flash electroretinography and retinal imaging with spectral domain optical coherence tomography.</p> <p><b>Results</b>: Central vision was central, steady, and maintained. There was bilateral myopic astigmatic refractive error. Fundus exam was notable for dark foveolar pigmentation, but no obvious abnormalities of either eye. Spectral domain optical coherence tomography cross sections through the fovea revealed a normal appearing photoreceptor outer nuclear layer but loss of the interdigitation signal between the photoreceptor outer segments and the apical retinal pigment epithelium. Retinoschisis involving the inner nuclear layer of both eyes and possible ganglion cell layer thinning were also noted. There was a detectable electroretinogram with similarly reduced amplitudes of rod- (white, 0.01 cd.s.m⁻²) and cone-mediated (3 cd.s.m⁻², 30 Hz) responses.</p> <p><b>Conclusion</b>: Photoreceptor outer segment abnormalities and retinoschisis may represent the earliest structural retinal change detected by spectral domain optical coherence tomography in patients with Cohen syndrome, suggesting a complex pathophysiology with primary involvement of the photoreceptor cilium and disorganization of the structural integrity of the inner retina.</p

Fleck-like lesions in <i>CEP290-associated</i> leber congenital amaurosis: a case series

To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 (CEP290-LCA) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition. This is a retrospective review of records of five patients with CEP290-LCA. Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths. All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals. We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.</p

Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

Abstract Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies